After shakedown off the New England coast and in Chesapeake Bay, Grayson joined Gwin, Meredith and Monssen in Destroyer Division 22 and on 28 August became temporary flagship of Destroyer Squadron 11 operating in the Caribbean from Guantánamo Bay. Two months later, she was transferred with her division to the North Atlantic patrol, operating between Argentia, Newfoundland and Hvalfjord, Iceland. Then, after ten months of this dreary duty, the division sailed with Hornet (CV 8) from Norfolk through the Panama Canal, clearing San Francisco on 2 April with Lt. Col. “Jimmy” Doolittle’s squadron of B-25s to bomb Japan.

Returning with the task force to Pearl Harbor on 25 April, the “G” continued on to Mare Island for repairs but was back at Pearl Harbor 15 July to escort Enterprise (CV 6) and Hornet to the South Pacific for the commencement of the Guadalcanal campaign. Thus began eight months of operation in the Solomon Islands area with highlights including the following:

On 24 August, operating in Enterprise’s Task Force 16 under RAdm. Kinkaid with North Carolina, Portland, Atlanta and destroyers Balch, Maury, Benham, Ellet and Monssen during the Battle of the Eastern Solomons, Grayson shot down two planes and damaged a third.

The next day, joining Saratoga’s Task Force 11 under RAdm. Fletcher, Grayson expended all her depth charges and claimed but was not credited with sinking a Japanese submarine.

On 18 October, after an extended search with Gwin and Seminole (AT 65), Grayson located and rescued 75 survivors from Meredith and Vireo (AT 144), who had been adrift in the Coral Sea for three days following Meredith’s sinking.

In February 1943, Grayson came under night attack from torpedo planes off San Cristobal but was not damaged.

In early 1943, DesDiv 22 survivors Gwin and Grayson were reassigned to depleted Destroyer Squadron 12, In April, however, Grayson again returned to the west coast for overhaul, thus missing much of the New Georgia operation. She arrived back in the Solomon Islands only in time to operate with ships of DesRon 21 in anti-barge sweeps up the “Slot,” destroying 4–6 Japanese barges on the evacuation route from Kolombangara on 30 September–3 October.

On 16 December, Grayson returned to Puget Sound Navy Yard for a third overhaul; then from March through August 1944 was attached to a reconstituted DesDiv 24 with Wilkes, Nicholson and Swanson, operating in the Solomon, Caroline, and Marshall Islands and supporting General MacArthur’s landings in the Admiralty Islands and jungle campaign in Dutch New Guinea.

On 1 September, Grayson was reassigned to Task Group 38 for carrier strikes against the Palau Islands prior to the landings there. On the 14th, with DesRon 12 flagship Farenholt and McCalla, she bombarded a radar station at Cape San Augustin at the mouth of Mindanao’s Davao Gulf, the first such action against a target in the Philippine Islands.

In October, the task force also struck Okinawa and the Philippines. On the 14th, Grayson was in formation with McCalla escorting cruisers Boston (CA 69) and Houston (CL 81) off Formosa, deep within range of enemy aircraft, when Houston was torpedoed. While Boston took her under tow, Grayson, Cowell and Boyd conducted rescue operations—the “G” picking up 194 men—and escorted the slow-moving “CripDiv” or “BaitDiv” until relieved two days later.

For seven months thereafter, the “G” operated from Saipan on radar picket and lifeguard duty before returning to the West Coast for a fourth time, arriving at Seattle in June 1945.

Overhauled one last time, Grayson took departure again for the war zone but arrived at Pearl Harbor only on 1 September. Then, after only brief training, she sailed for the east coast, passing through the Panama Canal on 8 October and standing into Charleston on 16 October. There on Navy Day, 27 October, she hosted over 5,000 visitors; there too she remained until decommissioned 4 February 1947 and placed in reserve in the 16th Fleet. Later she was transferred to Orange, TX, then to Galveston where she was stricken from the navy list on 1 June 1971 and eventually scrapped for $73,000.